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Title: Glucocorticoids and the programming of hepatic glucose metabolism
Author: Nyirenda, Moffat J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Since steroid hormones have well characterised programming properties, excessive fetal exposure to glucocorticoids in early in life may produce lifelong effects. In order to examine the role of glucocorticoids in the programming of glucose metabolism, fetal glucocorticoid load was increased by administration of dexamethasone, a poor substrate for 11β-HSD, during the different trimesters of rat pregnancy. Dexamethasone given selectively in the last week of pregnancy reduced birth weight by 10%, and produced hyperglycaemia and hyperinsulinaemia in the adult offspring. In addition, rats exposed to dexamethasone during the last week of intrauterine life had permanent increases in hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity). In contrast dexamethasone, when given in the first or second week of gestation, had no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. Similarly, administration of dexamethasone to pups postnatally did not alter glucose control in the adult animals. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis. In order to examine further the molecular basis for hepatic PEPCK overexpression, levels of liver enriched transcription factors known to co-operate with GR in stimulation of PEPCK gene transcription were analysed. Levels of hepatic nuclear factor (HNF)-1, HNF-4, and CCAAT/enhancer binding protein (C/EBP)α (but not C/EBPβ) did alter with prenatal dexamethasone treatment. However, unlike GR mRNA, expression of none of these factors correlated closely with changes in PEPCK level or hyperglycaemia. These studies have confirmed that in utero overexposure to glucocorticoids can programme hyperglycaemia which may be in part due to glucocorticoid mediated increase in hepatic gluconeogenesis, and provide support for the hypothesis that excessive fetal exposure to glucocorticoids underlies the link between low birth weight and disease in adulthood observed in human epidemiological studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available